1. Field of the Invention
The invention is directed to the use of specific 5-HT4 receptor agonist compounds for the treatment of cognitive disorders, in particular to the use of these compounds in combination with other agents, specifically acetylcholinesterase inhibitors for the treatment of Alzheimer's disease and other cognitive disorders.
2. State of the Art
The number of elderly people at risk of developing dementia is growing rapidly as life expectancy increases around the world. Alzheimer's disease is the most common cause of dementia in the elderly, accounting for 50-60% of all cases, according to some experts. In 2008, an estimated 5.2 million people were living with Alzheimer's disease in the United States alone, accounting for 13% of the US population aged 65 and over.
Alzheimer's disease is defined as progressive cognitive decline and impaired functional status inconsistent with normal aging. It is believed that deficits in the cholinergic system are a major contributor to the cognitive symptoms associated with Alzheimer's disease. Accordingly, the dominant pharmaceutical treatment for Alzheimer's disease provides modest symptomatic relief through the use of acetylcholinesterase inhibitors. These agents are believed to act by reducing the rate of acetylcholine degradation thus leading to increases in acetylcholine concentrations in the brain.
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that is widely distributed throughout the body, both in the central nervous system and in peripheral systems. At least seven subtypes of serotonin receptors have been identified and the interaction of serotonin with these different receptors is linked to a wide variety of physiological functions. The serotonergic system in the brain has been shown to be involved in cognitive processes. In particular, 5-HT4 receptors have been demonstrated to play a role in the neuronal mechanism of memory enhancement and cognitive processes in animal models. Activation of the 5-HT4 receptor enhances release of acetylcholine from cholinergic neurons, thus providing another potential approach to a pharmacological intervention that beneficially increases acetylcholine concentrations at synapses within the brain (Maillet et al. (2004) Current Alzheimer Research 1:79-85). Furthermore, it has been suggested that some 5-HT4 receptor agonist compounds may be used in the treatment of central nervous system disorders including cognitive disorders, behavioral disorders, mood disorders, such as depression and anxiety, and disorders of control of autonomic function.
Activation of the 5-HT4 receptor also stimulates α-secretase activity resulting in increased levels of soluble amyloid precursor protein alpha (sAPPα) which has neurotrophic and neuroprotective properties, and is also associated with cognitive enhancement preclinically. Beta amyloid (Aβ) is a peptide of 39-43 amino acids that appears to be the main constituent of amyloid plaques in the brains of Alzheimer's disease patients. Aβ is formed after cleavage of amyloid precursor protein by β- and γ-secretases. In preclinical studies, 5-HT4 receptor agonist-induced activation of α-secretase, and generation of sAPPα, reduces the level of Aβ. Such a reduction in Aβ levels is expected to be beneficial. Therefore, 5-HT4 receptor agonists offer the potential to provide both symptomatic and disease-modifying benefits (Lezoualc'h (2007) Experimental Neurology 205:325-329).
To date, no treatment that exploits the potential utility of the 5-HT4 mechanism for the treatment of cognitive disorders has been approved. Accordingly there remains a need for a treatment of memory dysfunction in people suffering from Alzheimer's disease that takes advantage of increases in acetylcholine concentrations and other potential benefits expected from use of a 5-HT4 receptor agonist agent.